Altered Receptor Specificity and Cell Tropism of D222G Hemagglutinin Mutants Isolated from Fatal Cases of Pandemic A(H1N1) 2009 Influenza Virus

Liu, Yan; Childs, Robert A.; Matrosovich, Tatyana; Wharton, Steve; Palma, Angelina S.; Chai, Wengang; Daniels, Rodney S.; Gregory, Victoria; Uhlendorff, Jennifer; Kiso, Makoto; Klenk, Hans Dieter; Hay, Alan J.; Feizi, Ten; Matrosovich, Mikhail

doi:10.1128/jvi.01639-10

Cited by 182 publications

(215 citation statements)

References 23 publications

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“…The 222D clone rarely binds to SAa2-3Gal, according to the results of an in vitro study. 33 This might explain why many more InfA-NP antigens were detected in pneumocytes in case 1 than in cases 2 and 4. (ii) GGT (G, glycine) was the major sequence and AAT (N, asparagine) was the minor sequence in the lung.…”

Section: Discussionmentioning

confidence: 99%

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

et al. 2012

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, were histopathologically analyzed. Hematoxylin-eosin staining, immunohistochemistry for type A influenza nucleoprotein antigen, and real-time reverse transcription-PCR assay for viral RNA were performed on formalin-fixed and paraffin-embedded specimens. In addition, the D222G amino acid substitution in influenza virus hemagglutinin, which binds to specific cell receptors, was analyzed in formalinfixed and paraffin-embedded trachea and lung sections by direct sequencing of PCR-amplified products. There were several histopathological patterns in the lung according to the most remarkable findings in each case: acute diffuse alveolar damage (DAD) with a hyaline membrane (four cases), organized DAD (one case), acute massive intra-alveolar edema with variable degrees of hemorrhage (three cases), neutrophilic bronchopneumonia (five cases) and tracheobronchitis with limited histopathological changes in alveoli (four cases). In two cases, the main findings were due to preexisting disease. Influenza virus antigen was only detected in the respiratory tract in 10 cases by immunohistochemistry. The antigen was detected in type II pneumocytes (three cases) in the epithelial cells of the trachea, bronchi and glands (six cases), and in the epithelial cells in both of the above (one case). The four cases with acute DAD presented with antigen-positive type II pneumocytes. In one case, the D222G substitution was detected in the lung as a major sequence, although 222D was prominent in the trachea, suggesting that selection of the viral clones occurred in the respiratory tract. In five

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Section: Discussionmentioning

confidence: 99%

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

et al. 2012

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“…The CT-Sw/1204 virus also became virulent in BALB/c mice known to express predominantly α2,3-sialic acid in their lungs (24), and demonstrated enhanced infectivity and growth in human lung tissues, indicating potentially productive pulmonary replication. Notably, severe viral pneumonia attributed to efficient virus attachment to α2,3-sialic acid glycoconjugates deep in the lungs have been observed in H5N1 (25) and HA 225G variants of the pH1N1 (5,(26)(27)(28)(29)(30) virus infections. Moreover, it has been demonstrated that avian-type receptor-binding ability because of HA 225G increased pathogenicity of the pH1N1 2009 virus in nonhuman primates (31).…”

Section: Discussionmentioning

confidence: 99%

Virulence and transmissibility of H1N2 influenza virus in ferrets imply the continuing threat of triple-reassortant swine viruses

Pascua

Song

Lee

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Efficient worldwide swine surveillance for influenza A viruses is urgently needed; the emergence of a novel reassortant pandemic H1N1 (pH1N1) virus in 2009 demonstrated that swine can be the direct source of pandemic influenza and that the pandemic potential of viruses prevalent in swine populations must be monitored. We used the ferret model to assess the pathogenicity and transmissibility of predominant Korean triple-reassortant swine (TRSw) H1N2 and H3N2 influenza viruses genetically related to North American strains. Although most of the TRSw viruses were moderately pathogenic, one [A/Swine/Korea/1204/2009; Sw/1204 (H1N2)] was virulent in ferrets, causing death within 10 d of inoculation, and was efficiently transmitted to naive contact ferrets via respiratory droplets. Although molecular analysis did not reveal known virulence markers, the Sw/1204 virus acquired mutations in hemagglutinin (HA) (Asp-225-Gly) and neuraminidase (NA) (Ser-315-Asn) proteins during the single ferret passage. The contact-Sw/1204 virus became more virulent in mice, replicated efficiently in vitro, extensively infected human lung tissues ex vivo, and maintained its ability to replicate and transmit in swine. Reverse-genetics studies further indicated that the HA 225G and NA 315N substitutions contributed substantially in altering virulence and transmissibility. These findings support the continuing threat of some field TRSw viruses to human and animal health, reviving concerns on the capacity of pigs to create future pandemic viruses. Apart from warranting continued and enhanced global surveillance, this study also provides evidence on the emerging roles of HA 225G and NA 315N as potential virulence markers in mammals.

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“…The HA D222G substitution was reported to alter receptor recognition from human-like α2,6-to avian-like α2,3-sialic acids. 10 The HH15-specific HA S202T substitution is localized within a highly variable epitope region and was suggested to have occurred rapidly during evolution of pH1N1 strains. 11 Further studies are needed to understand whether the HA S202T mutation affects receptor specificity or plays a role in pH1N1 pathogenicity.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

2009 pandemic H1N1 influenza A virus strains display differential pathogenicity in C57BL/6J but not BALB/c mice

Otte¹,

Gabriel²

2011

Virulence

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Altered Receptor Specificity and Cell Tropism of D222G Hemagglutinin Mutants Isolated from Fatal Cases of Pandemic A(H1N1) 2009 Influenza Virus

Cited by 182 publications

References 23 publications

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

Virulence and transmissibility of H1N2 influenza virus in ferrets imply the continuing threat of triple-reassortant swine viruses

2009 pandemic H1N1 influenza A virus strains display differential pathogenicity in C57BL/6J but not BALB/c mice

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